EP1003738A1 - Composes bicycliques servant de ligands pour les recepteurs 5-ht1 - Google Patents
Composes bicycliques servant de ligands pour les recepteurs 5-ht1Info
- Publication number
- EP1003738A1 EP1003738A1 EP98946322A EP98946322A EP1003738A1 EP 1003738 A1 EP1003738 A1 EP 1003738A1 EP 98946322 A EP98946322 A EP 98946322A EP 98946322 A EP98946322 A EP 98946322A EP 1003738 A1 EP1003738 A1 EP 1003738A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- pyridin
- compound
- nitrogen
- oxygen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003446 ligand Substances 0.000 title abstract description 8
- 102000035038 5-HT1 receptors Human genes 0.000 title description 2
- 108091005478 5-HT1 receptors Proteins 0.000 title description 2
- 125000002619 bicyclic group Chemical group 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000011282 treatment Methods 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 62
- 229910052757 nitrogen Inorganic materials 0.000 claims description 33
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 32
- 229910052760 oxygen Inorganic materials 0.000 claims description 32
- 239000001301 oxygen Substances 0.000 claims description 32
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 25
- 239000005864 Sulphur Chemical group 0.000 claims description 25
- 239000004202 carbamide Substances 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000005605 benzo group Chemical group 0.000 claims description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- TUPJECHPEGKXTN-UHFFFAOYSA-N 1-[3-(1-methylpiperidin-4-yl)-1-benzothiophen-5-yl]-3-(4-pyridin-4-ylnaphthalen-1-yl)urea Chemical compound C1CN(C)CCC1C(C1=C2)=CSC1=CC=C2NC(=O)NC(C1=CC=CC=C11)=CC=C1C1=CC=NC=C1 TUPJECHPEGKXTN-UHFFFAOYSA-N 0.000 claims description 4
- -1 C^alkyl Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- FEPOKSGWTVEWEG-UHFFFAOYSA-N 1-(3-chloro-4-pyridin-4-ylphenyl)-3-[3-(1-methylpiperidin-4-yl)-1-benzothiophen-5-yl]urea Chemical compound C1CN(C)CCC1C(C1=C2)=CSC1=CC=C2NC(=O)NC1=CC=C(C=2C=CN=CC=2)C(Cl)=C1 FEPOKSGWTVEWEG-UHFFFAOYSA-N 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims description 3
- FTLOEECOMIRAAA-UHFFFAOYSA-N 1-(2-chloro-4-pyridin-4-ylphenyl)-3-[3-(1-methylpiperidin-4-yl)-1h-indol-5-yl]urea Chemical compound C1CN(C)CCC1C(C1=C2)=CNC1=CC=C2NC(=O)NC1=CC=C(C=2C=CN=CC=2)C=C1Cl FTLOEECOMIRAAA-UHFFFAOYSA-N 0.000 claims description 2
- AWULZJOIPKEFME-UHFFFAOYSA-N 1-(3-chloro-4-pyridin-4-ylphenyl)-3-[3-(1-methylpiperidin-4-yl)-1h-indol-5-yl]urea Chemical compound C1CN(C)CCC1C(C1=C2)=CNC1=CC=C2NC(=O)NC1=CC=C(C=2C=CN=CC=2)C(Cl)=C1 AWULZJOIPKEFME-UHFFFAOYSA-N 0.000 claims description 2
- RWGKLSHDSQRTQM-UHFFFAOYSA-N 1-[3-(1-methylpiperidin-4-yl)-1h-indol-5-yl]-3-(3-methyl-4-pyridin-4-ylphenyl)urea Chemical compound C1CN(C)CCC1C(C1=C2)=CNC1=CC=C2NC(=O)NC1=CC=C(C=2C=CN=CC=2)C(C)=C1 RWGKLSHDSQRTQM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 2
- 230000036506 anxiety Effects 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- SWAWFRYFGQQACD-UHFFFAOYSA-N n-[3-(1-methylpiperidin-4-yl)-1h-indol-5-yl]-2-(4-pyridin-4-ylnaphthalen-1-yl)acetamide Chemical compound C1CN(C)CCC1C(C1=C2)=CNC1=CC=C2NC(=O)CC(C1=CC=CC=C11)=CC=C1C1=CC=NC=C1 SWAWFRYFGQQACD-UHFFFAOYSA-N 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 3
- HCUOEKSZWPGJIM-YBRHCDHNSA-N (e,2e)-2-hydroxyimino-6-methoxy-4-methyl-5-nitrohex-3-enamide Chemical compound COCC([N+]([O-])=O)\C(C)=C\C(=N/O)\C(N)=O HCUOEKSZWPGJIM-YBRHCDHNSA-N 0.000 claims 1
- YLDORFSTFAQNIC-UHFFFAOYSA-N 1-(2,3-dichloro-4-pyridin-4-ylphenyl)-3-[3-(1-methylpiperidin-4-yl)-1h-indol-5-yl]urea Chemical compound C1CN(C)CCC1C(C1=C2)=CNC1=CC=C2NC(=O)NC(C(=C1Cl)Cl)=CC=C1C1=CC=NC=C1 YLDORFSTFAQNIC-UHFFFAOYSA-N 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 28
- 208000015114 central nervous system disease Diseases 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 76
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000007787 solid Substances 0.000 description 23
- 239000000243 solution Substances 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 102000005962 receptors Human genes 0.000 description 18
- 108020003175 receptors Proteins 0.000 description 18
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 208000035475 disorder Diseases 0.000 description 10
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- DDXAGRCTJKBGRK-UHFFFAOYSA-N 4-pyridin-4-ylnaphthalen-1-amine Chemical compound C12=CC=CC=C2C(N)=CC=C1C1=CC=NC=C1 DDXAGRCTJKBGRK-UHFFFAOYSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 7
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 7
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- BHIKORUEKYQGCK-UHFFFAOYSA-N 3-(1-methylpiperidin-4-yl)-1-benzothiophen-5-amine Chemical compound C1CN(C)CCC1C1=CSC2=CC=C(N)C=C12 BHIKORUEKYQGCK-UHFFFAOYSA-N 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 5
- CKBJZDHVHHKARV-UHFFFAOYSA-N 3-(1-methylpiperidin-4-yl)-1h-indol-5-amine Chemical compound C1CN(C)CCC1C1=CNC2=CC=C(N)C=C12 CKBJZDHVHHKARV-UHFFFAOYSA-N 0.000 description 4
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 4
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- LHOQBUVINQBFDW-UHFFFAOYSA-N 2,3-dichloro-4-pyridin-4-ylaniline Chemical compound ClC1=C(Cl)C(N)=CC=C1C1=CC=NC=C1 LHOQBUVINQBFDW-UHFFFAOYSA-N 0.000 description 3
- CKKQZQNCMQYCCC-UHFFFAOYSA-N 2-(4-pyridin-4-ylnaphthalen-1-yl)acetic acid Chemical compound C12=CC=CC=C2C(CC(=O)O)=CC=C1C1=CC=NC=C1 CKKQZQNCMQYCCC-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- UBIOMSFKBWCPDF-UHFFFAOYSA-N 3-chloro-4-pyridin-4-ylaniline Chemical compound ClC1=CC(N)=CC=C1C1=CC=NC=C1 UBIOMSFKBWCPDF-UHFFFAOYSA-N 0.000 description 3
- ZXUDVMNLRAJGLC-UHFFFAOYSA-N 4-(5-nitro-1-benzothiophen-3-yl)pyridine Chemical compound C12=CC([N+](=O)[O-])=CC=C2SC=C1C1=CC=NC=C1 ZXUDVMNLRAJGLC-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 238000002825 functional assay Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000002464 receptor antagonist Substances 0.000 description 3
- 229940044551 receptor antagonist Drugs 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 206010008025 Cerebellar ataxia Diseases 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- DKQSRQLSDPYGCJ-UHFFFAOYSA-N n-phenylpyridin-4-amine Chemical compound C=1C=NC=CC=1NC1=CC=CC=C1 DKQSRQLSDPYGCJ-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000004031 partial agonist Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 2
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- FYWJWWMKCARWQG-UHFFFAOYSA-N 1,2-dichloro-3-isocyanatobenzene Chemical compound ClC1=CC=CC(N=C=O)=C1Cl FYWJWWMKCARWQG-UHFFFAOYSA-N 0.000 description 1
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- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates to novel compounds, processes for their preparation, and pharmaceutical compositions containing them.
- EPA 0733628 discloses a series of indole derivatives which are said to possess
- 5HTIF agonist activity 5HTIF agonist activity. These compounds are alleged to be of use in the treatment of migraine and associated disorders.
- EPA 0533266/7/8 disclose a series of benzanilide derivatives which are said to possess 5-HTj ) receptor antagonist activity.
- the 5-HTID receptor was subsequently found to consist of a pair of gene products originally designated 5-HTiD ⁇ and 5-HT ⁇ > ⁇ receptors which have more recently been reclassified as 5-HTID and 5-HTIJJ receptors, respectively. (Hartig, P.R. et al, Trends in Pharmacological Sciences 1992, Vol. 13, page 152, Hartig, P.R. et al., Trends in Pharmacological Sciences, 1996, Vol. 17, pagel03).
- the present invention therefore provides a compound of formula (I) or a salt thereof:
- R a is a group of formula (i)
- pi is phenyl, bicyclic aryl, a 5 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur;
- R 2 is hydrogen, halogen, Cj. ⁇ alkyl, C3_6cycloalkyl, C3_6cycloalkenyl, Ci.galkoxy,
- COC ⁇ _6alkyl ar y ⁇ acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO 2 RlO,
- P 2 and P ⁇ are independently phenyl, bicyclic aryl, a 5- to 7- membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;
- A is a bond or oxygen, S(O) m where m is 0, 1 or 2, carbonyl, or CH 2 or NR ⁇ where R ⁇ is hydrogen or Cj.galkyl;
- Rl is as defined above for formula (i) or is a 5 to 7-membered heterocyclic ring, containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by C ⁇ .galkyl, halogen or Cj.g alkanoyl;
- R2 and R ⁇ are as defined for R 2 in formula (i); and a and b are independently 1, 2 or 3;
- L is a group of formula
- V is oxygen or sulphur
- D is nitrogen, carbon or a CH group
- Y is -NH-or -NR ⁇ - and V is oxygen or sulphur; or (b) both Y and V are oxygen; or (c) Y is CH 2 and V is oxygen then pl is not phenyl within the definition of R a formula (i) and R a is not an unsubstituted biphenyl within the definition of formula (ii)
- Q is an optionally substituted 5- to 7- membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;
- RY is a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur;
- R D is hydrogen, halogen, hydroxy, Chalky., trifluoromethyl, Cj.galkoxy or aryl; or R D together with G forms a group W as defined above;
- C ⁇ _6alkyl groups whether alone or as part of another group may be straight chain or branched.
- the term 'acyloxy' is used herein to describe a group -OC(O)C ⁇ .galkyl.
- the term 'aryl' is used herein to describe, unless otherwise stated, a group such as phenyl.
- the term 'aralkyl' is used herein to describe, unless otherwise stated, a group such as benzyl.
- the bicyclic aryl group represented by pi, P 2 and/or P ⁇ , which may be partially saturated, is preferably naphthyl.
- bicyclic heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur include quinoline, isoquinoline, indole, benzofuran and benzothiophene rings.
- the heterocyclic groups can be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom.
- Examples of 5 to 7 membered heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur represented by pi, P 2 and/or P ⁇ include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrimidyl and pyrazinyl, preferably pyridyl.
- R! is preferably a halogen atom for example, fluorine, chlorine or bromine, and R2 and or R ⁇ are each preferably hydrogen, halogen for example a chloro group or a C ⁇ . galkyl group for example a methyl group.
- a and b are each preferably 1 or 2.
- A is preferably a bond.
- V is preferably oxygen.
- G D is preferably nitrogen and G is preferably a hydrogen atom or together with R D forms group- W, preferably -(CH 2 ) 2 -.
- Rb is preferably hydrogen or R D together with G forms group W referred to above.
- Q is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur.
- Q is a 5- or 6-membered ring containing one or two heteroatoms.
- Suitable optional substituents for the ring Q include groups R and R 2 as defined above, preferably C ⁇ alkyl, most preferably methyl.
- the group RY can be fully or partially saturated and can be linked to the group Q via a carbon atom or, when present, a suitable nitrogen atom.
- R v is 5 or 6 membered heterocyclic containing 1 or 2 nitrigen atoms.
- RY is a piperidinyl group.
- Particularly preferred compounds according to the invention include:- N-[3-(l-Methylpiperidin-4-yl)indol-5-yl]-N'-[4-(pyridin-4-yl)naphth-l-yl]-urea,
- Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p-toluenesulphonates.
- acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p-toluenesulphonates.
- Y is -CH 2 - or -O- and ⁇ is an appropriate leaving group, with a compound of formula (III)
- reaction in process (a) is conveniently effected in an organic solvent such as dichloromethane.
- the urea forming agent can be carbonyl diimidazole, triphosgene or phosgene, and carried out in an inert organic solvent such as dimethylformamide, tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
- the leaving group ⁇ 7 may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
- an inert organic solvent such as tetrahydrofuran or dichloromethane
- a base such as triethylamine or pyridine.
- the leaving group ⁇ 7 may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
- an inert organic solvent such as tetrahydrofuran or dichloromethane
- a base such as triethylamine or pyridine.
- Compounds of formula (I) can be converted into further compounds of formula (I) using standard techniques.
- Intermediate compounds of formula (II), (III), (IV), (V), (VI) and (VII) can be prepared using standard procedures known in the art.
- Carboxylic acid groups can be protected as esters.
- Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection is achieved using standard conditions.
- Serotonin (5-hydroxytryptamine; 5HT) receptors have been implicated in a number of pharmacological effects including mood disorders including depression, seasonal affective disorder and dysthymia, anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnesic disorders and age-associated memory impairment; disorders of eating behaviours, including anorexia nervosa and bulimia nervosa, sleep disorders (including disturbances of Circadian rhythm), motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.
- mood disorders including depression, seasonal affective disorder and dysthymia
- anxiety disorders including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder
- memory disorders including dementia, amnesic disorders and
- Serotonin receptor ligands have been shown to be of use in the treatment of emesis and nausea and may also be of use in endocrine disorders such as hyperlactinaemia, vasospasm (particularly in the cerebral vasculature), cerebellar ataxia and hypertension, as well as disorders of the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction and hypothermia. Ligands with high affinity for the 5HTj receptors are well recognised as having therapeutic utility for the treatment of the the above conditions.
- WO 95/31988 refers to the use of a 5-HTID receptor antagonist in co ⁇ juncton with a 5-HTIA receptor antagonist t ⁇ treat CNS, endocrine and GI disorders
- K. Rasmussen Annual Reports in Medicinal Chemistry, (1995) 30, 1) describes the utility of 5-HT ⁇ A receptor agonists and partial agonists in the treatment of various CNS disorders
- P. Trouillas Progress in Brain Research, C.I. de Zeeuw, P. Stara and J. Voogd, Eds. 1997, 144, 589)
- G. Maura J. Neurochemistry, 1996, 6 ⁇ , 202 propose that administration of agonist ligands selective for the 5-HT ⁇ A receptor or for both 5-HT ⁇ A ⁇ d 5-HTID receptors should provide effective treatment for human cerebellar ataxias.
- the present invention also provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of the aforementioned disorders.
- the invention provides a method of treating the aforementioned disorders which comprises administering an effective amount to a patient in need of such treatment of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof.
- the invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression.
- the affinities of the compounds of this invention for the 5HTIA > 5-HT ⁇ and 5-HTID receptors can be determined by the following radioligand binding assay.
- HEK 293 cells expressing 5-HT i A receptors (4 x 10 7 /ml) are homogenised in Tris buffer and stored in 1ml aliquots.
- CHO cells expressing 5-HT j ⁇ receptors (4 x 10 7 cells/ml) are homogenised in Tris buffer and stored in 1.5 ml aliquots.
- CHO cells expressing 5-HT ⁇ j) receptors (0.563 x 10 ⁇ /ml) are homogenised in Tris buffer and stored in 1 ml aliquots.
- pKi values are calculated from the IC50 generated by an iterative least squares curve fitting programme.
- the intrinsic activity of the compounds of this invention can be determined according to the following procedure. HEK293 cell membranes stably expressing human 5-HT i A receptors and CHO cell membranes stably expressing human 5-HTi g receptors are homogenised in HEPES/EDTA buffer and stored in 1ml aliquots, and [ 35 S]GTP ⁇ S binding studies are carried out essentially as described by Lazareno et al., (Life Sci., 1993, 52, 449) with some minor modifications.
- Membranes from 10 ⁇ cells are pre- incubated at 30°C for 30 minutes in 20 mM HEPES buffer (pH 7.4) in the presence of MgCl 2 (3 mM), NaCl (100 mM), GDP (10 ⁇ M) and ascorbate (0.2 mM), with or without test compounds.
- the reaction is started by the addition of 10 ⁇ l of [ 35 S]GTP ⁇ S (100 pM, assay concentration) followed by a further 30 minutes incubation at 30°C.
- Non-specific binding is determined using nonradiolabelled GTP ⁇ S (20 ⁇ M) added prior to the membranes.
- the reaction is terminated by rapid filtration through Whatman GF/B grade filters followed by 5 x 1 ml washes with ice cold HEPES (20 mM) /MgCl 2 (3 mM) buffer. Radioactivity is measured using liquid scintillation spectrometry. This procedure is hereafter referred to as the [35s]GTP ⁇ S functional assay.
- the compounds of formula (I) show high affinity for the 5W ⁇ A_, 5-HTI g and 5-HTID receptors. It has been found, using the [ 3 ⁇ S]GTP ⁇ S functional assay, that certain compounds of formula (I) appear to be antagonists whilst others appear to be agonists, partial agonists or inverse agonists. The difficulties in describing intrinsic activity of drugs acting at G protein coupled receptors is recognised in the art (Hoyer and Boddeke, Trends in Pharmocological Sciences, July 1993, [Vol. 14], page 270-275). We believe that however these ligands are classified according to this functional assay, the compounds of this invention will be useful antidepressants in vivo.
- the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, a selective serotonin reuptake inhibitor (SSRI) antidepressant.
- SSRI selective serotonin reuptake inhibitor
- the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents The tablets may be coated according to methods well known in normal pharmaceutical practice.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
- fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
- the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
- the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
- adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
- the composition can be frozen after filling into the vial and the water removed under vacuum.
- Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
- the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
- composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
- suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
- suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
- the following Examples illustrate the preparation of compounds of the invention.
- the mixture was then concentrated in vacuo to a gum, which was partitioned between 2M sodium hydroxide solution and dichloromethane.
- the aqueous layer was separated, adjusted to pH 0 with 6M hydrochloric acid and washed with dichloromethane; then adjusted to pH 7 by addition of aqueous potassium carbonate solution and extracted with dichloromethane.
- the dichloromethane extract was dried (Na 2 SO4) an ⁇ ⁇ concentrated in vacuo to give the title compound, which crystallised from ether as needles mp 210-215°C (465mg, 46%).
- reaction mixture was cooled and concentrated in vacuo to approx 150 ml volume, then acidified with 2M HC1 acid (200 ml) and shaken well with ethyl acetate (400 ml).
- the solid present was filtered off, shaken with 10% Na 2 CO3 solution and dichloromethane, and the organic layer separated, dried (Na 2 SO_ ⁇ ) and concentrated in vacuo to afford the title compound as an orange/yellow solid (2.3g, 56%).
- the title compound was prepared in a similar manner to Example 1 from 2,3-dichloro-4- (pyridin-4-yl)aniline (D9, 0.20g, 0.85 mmole), 5-amino-3-(l-methylpiperidin-4-yl)-lH- indole (D2, 0.15g, 0.66 mmole), triphosgene (O.lOg, 0.34 mmole) and triethylamine (0.30ml). This was obtained as a pink white solid (0.18g).
- Example 5 N-[3-(l-Methylpiperidin-4-yl)indol-5-yI]-4-(pyridin-4-yl)naphth-l-ylacetamide (E5)
- a stirred suspension of 4-(pyridin-4-yl)naphth-l-ylacetic acid (D7, 0.18g, 0.7 mmole) in dichloromethane (15ml) was treated with oxalyl chloride (0.18ml, 2.1 mmole), then stirred at room temperature for 3hours, before evaporating to dryness.
- the title compound was prepared in a similar manner to Example 1 from 4-(pyridin-4- yl)naphth-l -ylamine (D3, 0.16g, 0.7 mmole), 7-(l-methylpiperidin-4-yl)-l,2,3,5- tetrahydropyrrolo[2,3-fJindole (D6, 0.15g, 0.6 mmole), triphosgene (0.08g, 0.28 mmole) and triethylamine (0.25ml). This was obtained as a cream powder (0.1 lg).
- the title compound was prepared in a similar manner to Example 1 from 3-chloro-4- (pyridin-4-yl)aniline (prepared using a similar procedure to Description 11) (0.18g, 0.88 mmole), 5-amino-3-(l-methylpiperidin-4-yl)-lH-indole (D2, 0.15g, 0.66 mmole), triphosgene (O.lOg, 0.34 mmole) and triethylamine (0.3ml). This was obtained as a off- white powder.
- Example 1 as a white solid (41%).
- Examples 1, 3, 4, 8, 9, 10 and 12 had pKi values >8.0 at 5-HTi A, 5-HTIB and 5-HT 1D receptors.
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Abstract
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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GBGB9716804.1A GB9716804D0 (en) | 1997-08-09 | 1997-08-09 | Novel compounds |
GB9716804 | 1997-08-09 | ||
GBGB9801633.0A GB9801633D0 (en) | 1998-01-26 | 1998-01-26 | Novel compounds |
GB9801633 | 1998-01-26 | ||
PCT/EP1998/005116 WO1999007700A1 (fr) | 1997-08-09 | 1998-08-06 | Composes bicycliques servant de ligands pour les recepteurs 5-ht1 |
Publications (2)
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EP1003738A1 true EP1003738A1 (fr) | 2000-05-31 |
EP1003738B1 EP1003738B1 (fr) | 2003-11-19 |
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EP98946322A Expired - Lifetime EP1003738B1 (fr) | 1997-08-09 | 1998-08-06 | Composes bicycliques servant de ligands pour les recepteurs 5-ht1 |
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US (1) | US6391891B1 (fr) |
EP (1) | EP1003738B1 (fr) |
JP (1) | JP2001512727A (fr) |
CA (1) | CA2299286A1 (fr) |
DE (1) | DE69819903T2 (fr) |
WO (1) | WO1999007700A1 (fr) |
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WO1999031086A1 (fr) * | 1997-12-12 | 1999-06-24 | Smithkline Beecham Plc | Derives de quinoleinepiperazine et de quinoleinepiperidine, leur preparation et leur utilisation en tant qu'antagonistes combines des recepteurs 5-ht1a, 5-ht1b et 5-ht1d |
WO2000055139A2 (fr) * | 1999-03-12 | 2000-09-21 | Boehringer Ingelheim Pharmaceuticals, Inc. | Composes utiles en tant qu'agents anti-inflammatoires |
US6492393B1 (en) * | 1999-11-16 | 2002-12-10 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as anti-inflammatory agents |
WO2001087878A1 (fr) * | 2000-05-18 | 2001-11-22 | Daiichi Pharmaceutical Co., Ltd. | Nouveaux dérivés de benzothiophène |
WO2003032989A1 (fr) * | 2001-10-18 | 2003-04-24 | Boehringer Ingelheim Pharmaceuticals, Inc. | Composes d'uree benzo fusionnes 1,4-disubstitues utilises comme inhibiteurs des cytokines |
EP1608319A4 (fr) | 2003-04-03 | 2007-02-28 | Univ California | Inhibiteurs ameliores pour hydrolase epoxyde soluble |
EP1765311A4 (fr) | 2004-03-16 | 2009-04-29 | Univ California | Reduction de la nephropathie au moyen d'inhibiteurs d'hydrolase d'epoxyde soluble et d'epoxyeicosanoides |
NZ554555A (en) | 2004-10-20 | 2011-09-30 | Univ California | Cyclohexyl-urea derivatives as improved inhibitors for the soluble epoxide hydrolase |
TW200808723A (en) | 2006-03-13 | 2008-02-16 | Univ California | Conformationally restricted urea inhibitors of soluble epoxide hydrolase |
CN102083794A (zh) * | 2008-05-05 | 2011-06-01 | 安姆根有限公司 | 作为γ分泌酶调节剂的脲化合物 |
US9296693B2 (en) | 2010-01-29 | 2016-03-29 | The Regents Of The University Of California | Acyl piperidine inhibitors of soluble epoxide hydrolase |
RS57618B1 (sr) * | 2013-08-02 | 2018-11-30 | Pfizer | Heterobicikloaril rorc2 inhibitori i postupci za njihovu upotrebu |
WO2016120849A1 (fr) | 2015-01-30 | 2016-08-04 | Pfizer Inc. | Modulateurs de pyrrolopyridine substituée par un méthoxy de rorc2 et leurs méthodes d'utilisation |
EP3250561A1 (fr) | 2015-01-30 | 2017-12-06 | Pfizer Inc | Modulateurs indole de rorc2 substitués par sulfonamide et leurs procédés d'utilisation |
WO2017152117A1 (fr) * | 2016-03-03 | 2017-09-08 | Cornell University | Inhibiteurs ire1-alpha à petites molécules |
WO2022030589A1 (fr) * | 2020-08-05 | 2022-02-10 | 国立大学法人北海道大学 | Ligand contenant un composé de coordination monodenté d'urée et catalyseur de borylation le contenant |
MX2023009682A (es) | 2021-02-19 | 2023-10-30 | Sudo Biosciences Ltd | Inhibidores de tyk2 y sus usos. |
WO2022175752A1 (fr) | 2021-02-19 | 2022-08-25 | Sudo Biosciences Limited | Inhibiteurs de tyk2 et leurs utilisations |
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GB9119932D0 (en) * | 1991-09-18 | 1991-10-30 | Glaxo Group Ltd | Chemical compounds |
GB9119920D0 (en) * | 1991-09-18 | 1991-10-30 | Glaxo Group Ltd | Chemical compounds |
ES2162792T3 (es) | 1991-09-18 | 2002-01-16 | Glaxo Group Ltd | Derivados de benzanilida como antagonistas de 5-ht1d. |
UA41297C2 (uk) * | 1991-11-25 | 2001-09-17 | Пфайзер, Інк. | Похідні індолу, фармацевтична композиція і спосіб лікування |
IL106445A (en) | 1992-07-30 | 1998-01-04 | Merck Sharp & Dohme | History of 1,2,4-Trans-Triazole 4-Transform, Preparation and Pharmaceutical Preparations Containing Them |
CN1121348A (zh) * | 1993-04-22 | 1996-04-24 | 辉瑞研究及发展公司 | 吲哚衍生物作为5-ht1类激动剂用于治疗周期性偏头痛 |
WO1995006044A1 (fr) * | 1993-08-20 | 1995-03-02 | Smithkline Beecham Plc | Derives d'amide et d'uree en tant qu'antagonistes du recepteur 5ht1d |
EP0716649B1 (fr) | 1993-08-31 | 1998-09-09 | Pfizer Inc. | Derives de 5-arylindole |
GB9407447D0 (en) * | 1994-04-14 | 1994-06-08 | Glaxo Group Ltd | Chemical compounds |
GB2289465A (en) | 1994-05-19 | 1995-11-22 | Merck Sharp & Dohme | Five-membered heteroaromatic 5-HT receptor agonists |
AU694226B2 (en) * | 1994-05-19 | 1998-07-16 | Merck Sharp & Dohme Limited | Piperazine, piperidine and tetrahydropyridine derivatives ofindol-3-ylalkyl as 5-HT1D-alpha agonists |
CZ288897A3 (cs) * | 1995-03-20 | 1998-02-18 | Eli Lilly And Company | V poloze 5-substituovaný 3-(1,2,3,6-tetrahydropyridin-4-yl)indol a 3-(piperidin-4-yl)indol a farmaceutický prostředek, který je obsahuje |
US5846982A (en) | 1996-06-14 | 1998-12-08 | Eli Lilly And Company | Inhibition of serotonin reuptake |
-
1998
- 1998-08-06 DE DE69819903T patent/DE69819903T2/de not_active Expired - Fee Related
- 1998-08-06 US US09/463,704 patent/US6391891B1/en not_active Expired - Fee Related
- 1998-08-06 CA CA002299286A patent/CA2299286A1/fr not_active Abandoned
- 1998-08-06 JP JP2000506204A patent/JP2001512727A/ja active Pending
- 1998-08-06 WO PCT/EP1998/005116 patent/WO1999007700A1/fr active IP Right Grant
- 1998-08-06 EP EP98946322A patent/EP1003738B1/fr not_active Expired - Lifetime
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DE69819903D1 (de) | 2003-12-24 |
WO1999007700A1 (fr) | 1999-02-18 |
EP1003738B1 (fr) | 2003-11-19 |
DE69819903T2 (de) | 2004-11-11 |
JP2001512727A (ja) | 2001-08-28 |
US6391891B1 (en) | 2002-05-21 |
CA2299286A1 (fr) | 1999-02-18 |
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